Once HIV-1 enters the target cell, the first goal in the viral cycle is to integrate into the cellular chromosomes. The irreversible integration as a provirus allows HIV-1 to persist in the infected cell in a quiescent or latent stage that leads to viral escape from immune response and current antiviral treatment. HIV-1 replication is absolutely dependent on different cellular and viral factors that initiate viral expression, acting at the long terminal repeat of the integrated provirus. Accordingly, HIV-1 induces changes in the cellular environment to make possible an efficient replication and production of viral progeny. One main instigator of HIV-1 replication is the viral regulator Tat, which is absolutely required for efficient transcription and elongation of viral transcripts. For this purpose, Tat recruits several cellular proteins to make the chromatin structure accessible for the transcription machinery, to acquire the posttranslational modifications essential for its function, and to produce efficient viral replication. However, the host cell has also several antiviral mechanisms that may act at different steps of the viral cycle to thwart HIV-1 replication. To level the match, HIV-1 encodes accessory proteins, such as Vif and Vpu, which play important roles in HIV-1 pathogenesis by counteracting cellular antiviral factors. The increasing knowledge of viral protein interactions with host cell factors will be essential for the discovery of new targets that could be used to design new therapeutic strategies.